The mechanism of bone loss is not well understood, but in practical effect, the disorder arises from an imbalance in the formation of new healthy bone and the resorption of old bone, skewed toward a net loss of bone tissue. This bone loss includes a decrease in both mineral content and protein matrix components of the bone, and leads to an increased fracture rate of, predominantly, femoral bones and bones in the forearm and vertebrae. These fractures, in turn, lead to an increase in general morbidity, a marked loss of stature and mobility, and, in many cases, an increase in mortality resulting from complications.
Bone loss occurs in a wide range of subjects including postmenopausal women, patients who have undergone hysterectomy, patients who are undergoing or have undergone long-term administration of corticosteroids, patients suffering from Cushing's syndrome, and patents having gonadal dysgenesis.
Unchecked bone loss can lead to osteoporosis which describes a group of diseases which arise from diverse etiologies. The consequence of this loss of bone mass and resulting bone fracture is the failure of the skeleton to provide adequate structural support for the body.
Two of the most common types of osteoporosis are Postmenopausal and senile osteoporosis.
Postmenopausal Osteoporosis PA0 Senile Osteoporosis PA0 or a pharmaceutically acceptable solvate or hydrate thereof.
One of the most common types of osteoporosis is that associated with menopause. Most women lose between 20-60% of the bone mass in the trabecular compartment of the bone within 3-6 years after the cessation of menses. This rapid loss is generally associated with an increase of bone resorption and formation. However, the resorptive cycle is more dominant and the result is a net loss of bone mass.
Osteoporosis is a common and serious disease among postmenopausal women. There are an estimated 25 million women in the United States alone, who are afflicted with this disease. The results of osteoporosis are both personally harmful, and also account for a large economic loss due its chronicity and the need for extensive and long-term support (hospitalization and nursing home care) from the disease sequellae. This is especially true in more elderly patients. Additionally, osteoporosis is generally not thought of as a life threatening condition, but a 20-30% mortality rate is related with hip fractures in elderly women. A large percentage of this mortality rate can be directly associated with postmenopausal osteoporosis.
The most vulnerable tissue in the bone to the effects of postmenopausal osteoporosis is the trabecular bone. This tissue is often referred to as spongy bone and is particularly concentrated near the ends of the bone near the joints and in the vertebrae of the spine. The trabecular tissue is characterized by small osteoid structures which inter-connect with each other as well as the more solid and dense cortical tissue which makes up the outer surface and central shaft of the bone. This criss-cross network of trabeculae gives lateral support to the outer cortical structure and is critical to the biomechanical strength of the overall structure. In postmenopausal osteoporosis, it is, primarily, the net resorption and loss of the trabeculae which leads to the failure and fracture of the bone. In light of the loss of the trabeculae in postmenopausal women, it is not surprising that the most common fractures are those associated with bones which are highly dependent on trabecular support, e.g., the vertebrae, the neck of the weight bearing bones (femur) and the forearm. Indeed, hip fracture, collies fractures, and vetebral crush fractures are indicative of postmenopausal osteoporosis.
Presently, the only generally accepted method for the treatment for post menopausal osteoporosis is estrogen replacement therapy. Although this therapy frequently is successful, patient compliance is low, primarily due to the undesirable side-effects of estrogen treatment. Frequently cited side-effects of estrogen replacement therapy include reinitiation of menses, bloating, depression, and fear of breast or uterine cancer. In order to limit the known threat of uterine cancer in those women who have not undergone a hysterectomy, a protocol of estrogen and progestin cyclic therapy is often employed. This protocol is similar to that which is used in birth control regimens, and often is not tolerated by many women because of the side-effects characteristic of progestin.
More recently, certain antiestrogens, originally developed for the treatment of breast cancer, have been shown in experimental models of postmenopausal osteoporosis to be efficacious. Among these agents is raloxifene, which is undergoing clinical evaluation [see, e.g., U.S. Pat. No. 5,393,763; and Black, L. J., et al., J. Clin, Invest., 93:63-69 (1994)]. In addition, tamoxifene, a widely used clinical agent for the treatment of breast cancer, has been shown to increase bone mineral density in post menopausal women suffering from breast cancer [Love, R. R., et al., N. Engl. J. Med., 326:852-856 (1992)]. To date, none of the antiestrogens have been approved for use in postmenopausal osteoporosis.
Another therapy for the treatment of postmenopausal osteoporosis is the use of calcitonin. Calcitonin is a naturally occurring peptide which inhibits bone resorption and has been approved for this use in many countries [see, e.g., Overgaard, K., et al., Br. Med. J., 305:556-561 (1992)]. The use of calcitonin has been somewhat limited. Its effects are very modest in increasing bone mineral density and the treatment is very expensive. Equally problematic is the fact that the peptide must be given by parenteral administration.
Another therapy for the treatment of postmenopausal osteoporosis is the use of bis-phosphonates. These compounds were originally developed for use in Paget's disease and malignant hypercalcemia. They have been shown to inhibit the bone resorption activity of osteoclasts. Several compounds of this class are currently undergoing clinical evaluation and several have been approved for the treatment of postmenopausal osteoporosis and include etidronate, alendronate, and pamidronate. These agents may be helpful in the treatment of osteoporosis, but these agents also have potential liabilities which include osteomalacia, extremely long half-life in bone (greater than 2 years), and possible "frozen bone syndrome" (e.g., the cessation of normal bone remodeling).
Senile osteoporosis is similar to postmenopausal osteoporosis in that it is marked by the loss on bone mineral density and resulting increase in fracture rate, morbidity, and associated mortality. Generally, it occurs in later life, 70+ years. Although, in the past, it has been more common in females, with the advent of a more elderly male population, this disease is becoming a major factor in the health of both sexes. It is not clear what, if any, the role of hormones such as testosterone or estrogen have in this disease, and its etiology remains obscure.
Treatment of this disease has not been very satisfactory and there presently are no drugs approved for the treatment of senile osteoporosis. Hormone therapy, estrogen in women and testosterone men have shown equivocal results. Calcitonin and bis-phosphonates may be of some utility and are undergoing clinical evaluation at the present time, but none have been approved in the United States for this use.
An agent which would inhibit bone loss and, thus, retain bone mineral density and structural integrity of the skeleton, would be of great medical benefit.
Vanadium is a transition metal, element 23, and a member of the Vb elements. It is commonly found in a number of oxidation states including the (V) state (e.g., vanadate, sodium orthovanadate, and sodium metavanadate), and the (IV) state (vanadyl, including, for example, vanadyl sulfate). Vanadium has been considered to be an essential trace element for mammalian systems. However, its exact function, especially in humans, is unknown [see, e.g., Nielsen, F. H., Fed. Proc., 5: 123-132 (1986)].
More recently, there has been renewed interest in the pharmacology of Vanadium compounds in the area of glucose regulation, diabetes, and some forms of hypertension. The activity of orthovanadate in diabetes was reveiwed by Heyliger, C. E., et al., in Science, 227:1474-1477 (1985). It also has been discovered that vanadium (IV), specifically vanadyl sulfate, is effective in the treatment of experimental diabetes [see, Ramanadham, S., et al., Am. J. of Physiology, 257:H904-H911], certain chelates of vanadium (IV) are effective in treating experimental models of diabetes [see, e.g., Dai, S., et al., Pharmacology Comm., 3(4):311-321 (1993) and PCT WO 93/06811]. Dai, et al., also have disclosed that the vanadium (IV) compounds are less toxic and better absorbed via the oral route than either vanadate or vanadyl sulfate [Dai, S., et al., Pharmac. & Toxicol., 75:265-273 (1994)].